Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6](Cl)[N:5]=[C:4]([CH2:18][CH2:19][CH3:20])[N:3]=1.[C:21]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([O:8][CH2:9][CH2:10][OH:15])[N:5]=[C:4]([CH2:18][CH2:19][CH3:20])[N:3]=2)(=[O:32])=[O:33])=[CH:27][CH:26]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Reactant: CCCc1nc(Cl)c(Oc2ccccc2OC)c(Cl)n1
Product: CCCc1nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(Oc2ccccc2OC)c(OCCO)n1

Procedure:
By reacting 4,6-dichloro-5-(o-methoxyphenoxy)-2-propylpyrimidine with p-tert-butylphenylsulfonamide and thereafter with ethylene glycol Na, there was obtained p-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-propyl-4-pyrimidinyl]-benzenesulfonamide.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][C:11]=2[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[CH2:1]([C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][C:11]=2[C:12]=1[S:27]([C:24]1[CH:25]=[CH:26][C:21]([OH:20])=[CH:22][CH:23]=1)(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1ccc2oc(Cc3ccccc3)cc2c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: CCc1ccc2oc(Cc3ccccc3)c(S(=O)(=O)c3ccc(O)cc3)c2c1

Procedure:
Acylation of 2-benzyl-5-ethylbenzofuran with 4-methoxybenzenesulfonyl chloride followed by demethylation of the product thus formed as previously described gives 2-benzyl-5-ethyl-3-(4-hydroxyphenylsulfonyl)benzofuran.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.C(O)C.Br[C:15]1[CH:16]=[N:17][C:18]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=3)[C:23]([S:34][CH3:35])=[CH:22]2)=[N:19][CH:20]=1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[N:19][C:18]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=3)[C:23]([S:34][CH3:35])=[CH:22]2)=[N:17][CH:16]=1
Reactant: OB(O)c1ccccc1F
Reactant: COC(=O)c1ccc2c(SC)cn(-c3ncc(Br)cn3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COC(=O)c1ccc2c(SC)cn(-c3ncc(-c4ccccc4F)cn3)c2c1
Temperature: 90 °C

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.15 g, 0.13 mmol), 2-fluorophenylboronic acid (0.93 g, 6.64 mmol) and ethanol (40 mL) were added under an argon atmosphere to a mixture of 51b) (2.0 g, 5.3 mmol) in DME (40 mL) and 2M sodium carbonate solution (5.3 mL). The resulting mixture was heated at 90° C. for 3 h and then filtered through a pad of celite that was subsequently rinsed with dichloromethane (2×50 mL). The filtrate was concentrated and the remnant purified by column chromatography [100-200 mesh silica; dichloromethane/hexane=1:1]. White solid. Yield: 2.0 g (96% of theory). HPLC-MS (method 5): Rt=4.41 min; m/z [M+H]+=394
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:25]([C:28]2[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:6]2[NH:10][C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])=[N:8][C:7]=2[CH:24]=1.C(=O)(O)[O-:40].[Na+:43]>C(COC)OC.O>[Na+:43].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:25]([C:28]2[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)(=[O:26])=[O:27])[C:6]2[NH:10][C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)(=[O:40])=[O:12])=[N:8][C:7]=2[CH:24]=1
Reactant: COc1cc(S(=O)(=O)c2ccc(OCC(=O)O)cc2)c2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(S(=O)(=O)c2ccc(OCC(=O)[O-])cc2)c2[nH]c(S(=O)(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 85.8 %

Procedure:
To a suspension of the sulfoxide acid (4.47 g, 0.008 mol) in glyme (75 mL) was added a solution of sodium bicarbonate (0.672 g, 0.008 mol) in water (50 mL). The reaction mixture was extracted with ethyl acetate (4×50 mL). The combined organic layers were back extracted with water (2×25 mL). The combined aqueous layers were lyophilized to give 4.1 g (88%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=O)[CH2:3]1.C[N:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=C([N+]([O-])=O)C1=O.N>>[CH3:1][CH:2]1[CH2:3][C:4]2[N:10]=[CH:15][C:14]([N+:16]([O-:18])=[O:17])=[CH:13][C:5]=2[CH2:6][CH2:7]1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Reactant: CC1CCCC(=O)C1
Agent: N
Product: CC1CCc2cc([N+](=O)[O-])cnc2C1
Yield: 53.7 %

Procedure:
3-Methylcyclohexanone (0.56 g, 4.99 mmol) was mixed with 1-methyl-3,5-dinitro-2-pyridone (1.00 g, 5.02 mmol) in 1M methanolic ammonia (50 mL, 50 mmol) and heated at reflux overnight. The solvent was evaporated off and the residue was suspended in CHCl3 and flash chromatographed over silica gel (43 g) eluting with EtOAc/hexane (1:10) to afford a white solid (515 mg, 63% yield): mp 55-56° C.
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH2:15][CH2:16][CH2:17][CH:18]3[N:23]([CH3:25])[CH3:24])C(=O)C2=CC=CC=C12>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][CH:18]2[N:23]([CH3:24])[CH3:25]
Reactant: CN(C)C1CCCc2c(OCCCN3C(=O)c4ccccc4C3=O)cccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(C)C1CCCc2c(OCCCN)cccc21

Procedure:
4.4 ml of 99% hydrazine hydrate are added to a stirred solution of 5-(3-phthalimidopropoxy)-1-dimethylamino-1,2,3,4-tetrahydronaphthalene (26.8 g prepared in the preceding step) in absolute ethanol (270 ml). The reaction mixture is stirred and heated to reflux for 3 hours, allowed to cool, filtered and the filtrate evaporated in vacuo. The yellow residue is triturated in 5% HCl (250 ml), the suspension filtered and the solid washed with 5% HCl. The clear yellow filtrate is extracted with diethyl ether. The aqueous acidic layer is made strongly alkaline with 50% NaOH solution, resulting in an oily precipitate which is extracted with diethyl ether. The combined organic extracts are dried over sodium sulfate, filtered and the filtrate evaporated in vacuo, yielding 14.7 g of a light yellow oil identified by NMR as the desired 3-aminopropoxy compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)C(OC)=O.[CH3:21]C1C=C(N)C2C=NNC=2C=1.IC1C=CC=CC=1>>[CH3:21][C:9]1[CH:10]=[C:2]([NH2:1])[C:3]2[CH:4]=[N:5][N:6]([C:11]3[CH:20]=[CH:19][CH:18]=[CH:13][CH:12]=3)[C:7]=2[CH:8]=1
Reactant: Cc1cc(N)c2cn[nH]c2c1
Reactant: COC(=O)c1cccc(-n2ncc3c(N)cccc32)c1
Solvent: Ic1ccccc1
Product: Cc1cc(N)c2cnn(-c3ccccc3)c2c1

Procedure:
Similarly prepared to Intermediate 9 from 6-methyl-1H-indazol-4-amine and iodobenzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][C@H:16]([OH:18])[CH2:15][CH2:14][C@H:13]1[CH2:12][S:11][C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:9]2.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][C@H:16]([OH:18])[CH2:15][CH2:14][C@H:13]1[CH2:12][S:11][C:10]([N:19]([CH2:33][C:32]1[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=1)[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[N:9]2
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)C[C@H](O)CC[C@H]2CS1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)C2=N[C@@]3(c4ccccc4F)C[C@H](O)CC[C@H]3CS2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (±)-[(4aR*,7R*,8aS*)-8a-(2-fluorophenyl)-7-hydroxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in Preparation Example 58-(8) (500 mg) was dissolved in DMF (10 mL), and the mixture was cooled in an ice bath under a nitrogen atmosphere. p-Methoxybenzyl chloride (161 μL, specific gravity: 1.154 g/cm3) and potassium carbonate (247 mg) were added thereto, followed by stirring for one hour. Thereafter, the reaction solution was warmed to room temperature and stirred for 19 hours. Ethyl acetate and water were added to the reaction solution, followed by further stirring. Then, the aqueous layer was separated. The organic layer was sequentially washed with a saturated ammonium chloride solution, water and brine. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography to obtain the title compound (541 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[CH3:22][C:23]([C:26]1[S:27][CH:28]=[C:29]([CH2:31][NH2:32])[N:30]=1)([CH3:25])[CH3:24]>>[C:23]([C:26]1[S:27][CH:28]=[C:29]([CH2:31][NH:32][C:14]([C:12]2[CH:11]=[CH:10][C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[N:30]=1)([CH3:25])([CH3:22])[CH3:24]
Reactant: CC(C)(C)c1nc(CN)cs1
Reactant: O=C(O)c1ccc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Product: CC(C)(C)c1nc(CNC(=O)c2ccc(OCC3CC3)c(-c3ccc(Cl)cc3)n2)cs1

Procedure:
The title compound was synthesized in analogy to Example 41, using 6-(4-Chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (example AW) and 2-(1,1-dimethylethyl)-4-thiazolemethanamine (CAN 937656-81-0) as starting materials; LC-MS (UV peak area/ESI) 97.7%, 456.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.[C:30](Cl)(Cl)=[S:31].[N:34]1([C:39]([CH2:41][CH2:42][CH2:43][NH2:44])=[O:40])[CH:38]=[CH:37][N:36]=[CH:35]1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:30]([NH:44][CH2:43][CH2:42][CH2:41][C:39]([N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)=[O:40])=[S:31])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: NCCCC(=O)n1ccnc1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NCCCC(=O)n4ccnc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 17.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (56 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (50 mg) was then added to the solution, and the mixture was stirred at room temperature for 7 hr. Next, 3-(1-imidazoyl)propylamine (50 mg) was added thereto, and the mixture was further stirred at room temperature for 13 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (16 mg, yield 18%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]2)=[CH:29][CH:28]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC1
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 75.5 %

Procedure:
To a suspension of crude 6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (423 mg, 1.5 mmol) in N,N-dimethylformamide (3 mL) is added 4-(4-Methyl-piperazin-1-yl)-phenylamine (290 mg, 1.5 mmol). The reaction mixture is shaken at 115° C. for 1.5 hours. Upon cooling to room temperature and addition of 2 mL of water, the product precipitated out. The precipitate is then filtered off, washed with water, and dried to yield 0.5 g of crude 6-bromo-4-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-4H-isoquinoline-1,3-dione, which is used as such for the next reaction.
Reaction SMILES: C(O)(=O)C.[C:5]1([NH:11][NH2:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:13][C:14](=O)[CH2:15][CH3:16]>C(O)C>[CH3:13]/[C:14](=[N:12]\[NH:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)/[CH2:15][CH3:16]
Reactant: CCC(C)=O
Reactant: NNc1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: CC/C(C)=N/Nc1ccccc1

Procedure:
Add acetic acid (1.00 mL, 17.45 mmol) and phenyl hydrazine (1.98 mL, 20.00 mmol) to a solution of 2-butanone (2.15 mL, 24.00 mmol) in ethanol (90 mL) at room temperature. Stir the reaction for 1 hr., then remove the solvents in vacuo to give N-[1-methyl-prop-(E)-ylidene]-N′-phenyl-hydrazine as a crude orange oil (3.21 g, 99%). MS (ES): m/z=163 [M+H]+.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[C:9]([CH2:10][OH:11])=[CH:8][CH:7]=[CH:6][N:5]=1>C(O)(=O)C>[NH2:3][C:4]1[C:9]([CH2:10][OH:11])=[CH:8][C:7]([Br:1])=[CH:6][N:5]=1
Reactant: Nc1ncccc1CO
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1ncc(Br)cc1CO

Procedure:
Bromine (10.4 mL, 202 mmol) was added dropwise over 1 hour to a solution of 2-amino-3-(hydroxymethyl)pyridine (25.1 g, 202 mmol) in acetic acid (500 mL) at room temperature. After complete addition the reaction mixture was stirred for an extra hour. After concentration to dryness, the residue was partitioned between 1M Na2CO3 (750 mL) and ethyl acetate (500 mL). The aqueous layer was separated and extracted one more time with ethyl acetate (500 mL). The combined organic phases were washed with a saturated solution of sodium chloride (500 mL), dried over sodium sulfate, filtered and concentrated to dryness. After trituration of the residue in DCM/heptane and extra washing with DCM the title product was obtained as a light yellow solid (30.0 g, 70%, py 97.3%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)#[N:2].[SH2:16]>CO.C(N(CC)CC)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)(=[S:16])[NH2:2]
Reactant: S
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccc(-c2ccccc2C(N)=S)cc1
Reaction time: 72 h

Procedure:
First, 2.00 g of 2-cyano-4'-methyl-1,1'-biphenyl was dissolved in a mixture of 15 ml of methanol and 4.18 g of triethylamine, and hydrogen sulfide gas was bubbled thereinto at room temperature to the point of saturation. After keeping at room temperature for 3 days, the solution was kept at 50° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate containing 1% hydrochloric acid. The organic layer was concentrated to give 2.18 g of 2-thiocarbamoyl-4'-methyl-1,1'-biphenyl. Yield, 92%; m.p., 111°-115° C.; m/z, 227
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:7]([CH2:20][C:21](O)=[O:22])[C:6]=2[C:5]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[C:21](=[O:22])[CH2:20][N:7]3[C:6]=2[C:5]([CH:24]([CH2:25][CH3:26])[CH2:27][CH3:28])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(Cl)cc3Cl)n(CC(=O)O)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CC(=O)N3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of {4-chloro-2-[(2,4-dichlorophenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl}acetic acid (Reference Example 21; 294 mg, 0.667 mmol) in N,N-dimethylformamide (3 mL) were added triethylamine (0.11 mL, 0.800 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153 mg, 0.800 mmol), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water, and the suspension was stirred at room temperature for 1.5 hr. The resulting solid was collected by filtration and washed with water. The crystal was recrystallized from diisopropyl ether-n-hexane to give 160 mg (0.378 mmol, 57%) as a colorless crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][N:33]([CH2:36]C)[CH2:34]C)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[CH2:43][C:44](Cl)=[O:45]>>[CH3:34][N:33]([CH3:36])[CH2:32][CH2:31][O:30][C:26]1[CH:25]=[C:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:44](=[O:45])[CH2:43][C:39]5[S:38][CH:42]=[CH:41][CH:40]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCN(CC)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)c1
Reactant: O=C(Cl)Cc1cccs1
Product: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1
Yield: 57 %

Procedure:
The title compound was synthesized from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-{[2-(diethylamino)ethyl]oxy}phenyl)-2-pyrimidinamine using acylation with 2-thienylacetyl chloride as described in Example 10, Step E to yield a light brown solid in 57% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.8 (s, 5H) 3.8 (d, J=0.9 Hz, 3H) 3.9 (s, 1H) 4.2 (s, 1H) 6.5 (d, J=5.3 Hz, 1H) 6.6 (s, 1H) 6.9 (m, 6H) 7.1 (s, 3H) 7.2 (s, 1H) 7.4 (m, 1H) 7.6 (s, 1H) 7.7 (s, 1H) 7.9 (s, 1H) 8.2 (d, J=5.5 Hz, 1H) 8.5 (s, 1H) 8.8 (m, 1H) 9.6 (s, 1H) 10.4 (s, 1H). ES-LC/MS m/z 590 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:37])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C@H:18]([NH:20][CH2:21][C@@H:22]([C:24]2[CH:25]=[N:26][C:27]([N:30]3C(C)=CC=C3C)=[CH:28][CH:29]=2)[OH:23])[CH3:19])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.NO>C(O)C>[NH3:8].[NH2:30][C:27]1[N:26]=[CH:25][C:24]([C@@H:22]([OH:23])[CH2:21][NH:20][C@H:18]([CH3:19])[CH2:17][C:13]2[CH:12]=[C:11]([CH2:10][C:9]([NH:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:37])[CH:16]=[CH:15][CH:14]=2)=[CH:29][CH:28]=1
Reactant: Cc1ccc(C)n1-c1ccc([C@@H](O)CN[C@H](C)Cc2cccc(CC(=O)NCc3ccccc3)c2)cn1
Agent: Cl
Agent: NO
Solvent: CCO
Product: C[C@H](Cc1cccc(CC(=O)NCc2ccccc2)c1)NC[C@H](O)c1ccc(N)nc1
Product: N
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.3 %

Procedure:
A solution of N-Benzyl-2-[3-((2R)-2-{(2R)-2-[6-(2,5-dimethyl-pyrrol-1-yl)-pyridin-3-yl]-2-hydroxy-ethylamino}-propyl)-phenyl]-acetamide (preparation 1, 148 mg, 0.30 mmol) in ethanol (5 ml) was treated with hydroxylamine hydrochloride (103 mg, 1.48 mmol) and the resulting mixture heated to 85C. for 48 hours. The reaction was cooled to room temperature and passed through a Strong Cation Exchange column eluting with methanol followed by 2N ammonia in methanol to elute the product. Further purification by flash column chromatography eluting with dichloromethane:methanol: 880 ammonia (97:3:0.5 changing to 90:10:1 by volume) gave the title compound as a pale yellow solid (36 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]3[CH2:24][N:23]([CH3:25])[C:22]4[N:26]=[CH:27][CH:28]=[CH:29][C:21]=4[CH:20](O)[C:19]=3[CH:31]=1)[CH:6]=[CH:5]2.Cl.[CH2:33]([O:35][C:36](=[O:41])[C@H:37]([CH2:39][SH:40])[NH2:38])[CH3:34].FC(F)(F)C(O)=O>ClCCl>[CH2:33]([O:35][C:36](=[O:41])[CH:37]([NH2:38])[CH2:39][S:40][CH:20]1[C:19]2[CH:31]=[C:15]([O:14][CH2:13][C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][C:11]([F:12])=[C:2]([F:1])[CH:3]=4)[N:8]=3)[CH:16]=[CH:17][C:18]=2[CH2:24][N:23]([CH3:25])[C:22]2[N:26]=[CH:27][CH:28]=[CH:29][C:21]1=2)[CH3:34]
Reactant: CCOC(=O)[C@@H](N)CS
Reactant: CN1Cc2ccc(OCc3ccc4cc(F)c(F)cc4n3)cc2C(O)c2cccnc21
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(N)CSC1c2cc(OCc3ccc4cc(F)c(F)cc4n3)ccc2CN(C)c2ncccc21
Temperature: 45 °C
Reaction time: 16 h

Procedure:
A mixture of 6.6 g (15.7 mmol) of the product from Example 21, step 5, 6.0 g (32.3 mmol) of L-cystein ethyl ester hydrochloride and 136 ml of trifluoroacetic acid in 198 ml of dichloromethane is stirred at 45° C. for 16 hr. The solvent is evaporated and the residue partitioned between sat. NaHCO3 and chloroform. The organic layer is washed with water, dried and concentrated, giving an oil, which solidifies with the aid of diisopropyl ether/petroleum ether. Yield 7.9 g (91%).
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[S:33]([NH2:36])(=[O:35])=[O:34]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:36][S:33]([C:29]3[S:28][CH:32]=[CH:31][CH:30]=3)(=[O:35])=[O:34])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: NS(=O)(=O)c1cccs1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2cccs2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 2-thiophenesulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method A described hereinabove. Yield (27%); 1H NMR (d6-DMSO) δ 12.34 (br s, 1H), 7.99 (m, 1H), 7.76 (m, 1H), 7.39-7.08 (m, 14H), 6.85 (d, J=8.4 Hz, 2H), 6.41 (d, J=15.7 Hz, 1H), 2.36 (q, J=7.3 Hz, 2H), 0.82 (t, J=7.3 Hz, 3H); APcI m/z: 500 (M+H+).
Reaction SMILES: [CH2:1]([N:8](C)[C:9]1[CH:10]=[C:11]([CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[OH:24])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:24][C:14]1[C:13]2[C:18](=[C:9]([NH:8][CH3:1])[CH:10]=[C:11]([CH2:25][N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH:12]=2)[N:17]=[CH:16][C:15]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: [H][H]
Reactant: CCOC(=O)c1cnc2c(N(C)Cc3ccccc3)cc(CN3CCOCC3)cc2c1O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cnc2c(NC)cc(CN3CCOCC3)cc2c1O
Yield: 70.5 %

Procedure:
A mixture of ethyl 8-[benzyl(methyl)amino]4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxylate (500 mg, 1.15 mmol), 10% palladium charcoal (0.25 g) in ethanol (100 mL) is hydrogenated (50 psi initial hydrogen pressure) until HPLC shows that all the starting material has been reduced (2.5 h). The solution is filtered, the solvent removed, and the residual oil is applied in chloroform to a silica gel column which is eluted with 5-10% methanol/chloroform. After elution of a small amount of ethyl 4-hydroxy-8-(methylamino)-6-methyl-3-quinolinecarboxylate, the title compound (280 mg) is obtained.